Pharmacology Flashcards
(87 cards)
1
Q
Define pharmacology?
A
-The study of the effect of DRUGS on the function of living systems
2
Q
what do pharmacologists do?
A
- Discover and develop new medicines
- Improve drug effectiveness and reduce unwanted side effects
- Understand individual variation in drug response
- Understand why some drugs cause tolerance or addiction
3
Q
what are the 2 major branches of pharmacology?
A
1)Pharmacodynamics
2)Pharmacokinetics
4
Q
why do we need to understand the physiology and pathophysiology of how diseases come about?
A
so we can design drug targets
5
Q
Define a drug and name the 2 types
A
A drug is a substance that when introduced to the body, it produces a biological effect for an intended purpose.
1)Therapeutic - treat, prevent or cure disease
2)lifestyle drugs - (non-medicinal) caffeine, street drugs, performance-enhancing drugs
6
Q
define a medicine
A
A medicine is a substance preparation that contains one or more drugs, administered with the intention of producing a therapeutic effect.
medicines contain other substances (solvents, stabilisers etc) that make them more convenient to use e.g. a tablet
7
Q
can a drug be poison?
A
yes - a drug can be INTENDED to have harmful effects on the body
“all drugs are poison, depends on the dose”
8
Q
list 5 places drugs come from
A
1)Natural products
2)changing structure of an existing molecule
3)serendipity (“by accident”)
4)rational/informed drug design (studying disease)
5)adapting an existing drug for a new therapy (repurposing)
9
Q
HOW DO DRUGS WORK ?
How does a tiny capsule or injection have such a large effect on the body?
A
- Molecules in an organism vastly out number the amount of drug molecules.
- if there is RANDOM drug distribution throughout the body (e.g. drug goes everywhere not just specific place its needed) then there is NO pharmacological effect.
- if there is NON-UNIFORM drug distribution
e.g. Drug interacts with a cellular molecule only expressed on a specific tissue of interest then there IS a pharmacological effect
10
Q
what is magic bullet also known as?
A
drug targets
11
Q
define the 2 branches of pharmacology
A
-pharmacodynamics (effect of the drug on the body)
-pharmacokinetics (effect of the body on the drug)
12
Q
what does pharmacodynamics investigate?
A
- mechanisms of drug action, including the molecular, cellular, and physiological effects of drug (the response)
- relationship between drug concentration and effect.
-how to make medicines safe, effective and reducing side effects
13
Q
what are the 2 things that happen when you take a drug?
A
1)Physiological Exposure - Enters the blood stream (systemic circulation)
2)Physiological Clearance - Detoxified and excreted (liver and kidney)
14
Q
what are drug targets?
A
molecules (often proteins), where the
function can be modulated by a drug
to produce a biological effect
15
Q
what are the 4 types of drug targets and where are they most commonly found?
A
- Receptors
- Ion channels
- Transporters
- Enzymes
most found embedded within cellular membrane, some found intracellular. some exceptions such as antibodies are found extracellular (outside membrane)
16
Q
what does Drug–target interaction mean?
A
describes the different ways a drug interacts with a target to produce a biological effect.
- determined by intermolecular forces, steric match, and the types of bonds formed
17
Q
what does Structure–activity relationship mean?
A
describes the unique relationship between the structural characteristics of a drug and specific amino acids in a target protein binding site, and
the resultant biological effect.
(does the structure of the drug fit in the target binding site (active site))
these structures can be manipulated during drug design to manage side effects etc and create best drug possible
18
Q
where do drug-target interactions occur?
A
- Drug-target interactions may occur at the active/orthostatic site (endogenous interactions occur) or allosteric site elsewhere on the drug target.
- Drugs can bind to their targets reversibly or irreversibly depending on the type of bonds formed.
19
Q
what is affinity?
A
binding strength of a drug to a target / Ability to bind to receptors and form drug-receptor complex
20
Q
what is efficacy?
A
ability of a drug to elicit a response once bound to a drug target
(structure activity also plays a part in this because if you change certain parts of side chains of your drug molecule, you often can either enhance or diminish the response)
(basically whether you get a response or not/Ability to switch receptor to its active form and produce a response)
21
Q
what is the drug (or endogenous compound e.g. neurotransmitter) called if you DO get a response?
A
agonist
22
Q
what is the drug (or endogenous compound e.g. neurotransmitter) called if you DONT get a response?
A
antagonist
23
Q
what is the definition of agonist?
A
endogenous or exogenous molecules that have affinity for and efficacy at a receptor to produce a biological response.
24
Q
what is the definition of antagonist?
A
Antagonists: molecules that have affinity for a receptor to limit the effect of agonists but lack efficacy
they form drug receptor complex but not response as no efficacy
Antagonists basically block the effects of agonists (as agonists actually produce a response).
25
what is drug selectivity?
a drug's ability to discriminate between drug targets
– Determined by affinity and efficacy for one target vs another (does it produce an effect?)
– Each drug target recognises only a small number of molecules, all of which will have some structural similarity
26
can you have multiple receptors for the same drug?
yes, you can have multiple receptors for the same drug, but the drug may have a stronger efficacy (biological response) for a particular one.
27
what are subtypes?
Different receptors for the same endogenous agonist
28
define potency and what it's dependent on
Potency is the amount of a drug, expressed as the concentration or dose, needed to produce a defined effect.
strong potency=you will need very small concentration to produce biological effect
weak potency=you will need much higher concentration to produce effect
– Dependant on
* Target affinity and efficacy
* Tissue receptor number and drug availability
29
why is the synapse a good system to evaluate drug action?
The synapse is an excellent physiological system to visualise drug action since a synapse can express all 4 drug targets
30
what is the role of receptors? and where are most found
In pharmacology, receptors are proteins whose function is to recognise and respond to endogenous chemical signals.
most found embedded in the lipid bilayer of cell membrane
31
how many types of receptors are there are what are they and how fast are they?
4
1)ligand gated ion channels (miliseconds)
2)G-protein coupled receptor (seconds)
3)kinase-linked receptors (hours)
4)nuclear receptor (hours)
each receptor receptor recognises only a small number of molecules, all of which will have some structural similarity
32
what can agonists and antagonists only be used for describing?
receptors! not the other three types of drug targets
33
how do ligand gated ion channels work?
*Ligands/drugs bind to an extracellular domain
* Part of each subunit (the pore domain-dark purple- middle part) forms a hydrophilic (water filled) channel to selectively allow ions to flow through the membrane
Basically, when drug binds to ion channel receptor, it opens channel and allows ions to flow through. When drug is not bound the channel is closed.
34
how do voltage gated ion channels work?
Voltage gated ion channel opens and closes based on membrane potential. Voltage between intracellular and extracellular membranes. When the membranes are not In equilibrium, the plug moves away and the channel opens
35
what is the regulation of ions useful for in the body?
Contraction
Electrical excitation (stimulus in brain)
Secretion signalling
36
what 2 things can happen when combining drugs and ion channels
1)they can block the ion channel – preventing any ions from going through
2)modulating the ion channels – increase or decrease amount of ions going through
almost all ion channel drugs used therapeutically are ion channel blockers.
37
what are the properties of G-protein coupled receptors?
-single protein polypeptide
-7 transmembrane domains (alpha helices)
-ligand binds either to extracellular domain or within transmembrane domain (depending on type)
38
how does a G protein work?
-G protein is a guanine-nucleotide binding protein
-made up of 3 subunits alpha, beta and gamma (y)
-when ligand binds to the protein, the alpha subunit binds to GTP and disassociates from the complex
-alpha subunit is then free to activate target ion channel or enzyme
Dependent on the G protein, it is not always a positive response! But this is good because it allows us to balance our physiological processes
G proteins are rapid
39
what are transporters/carriers and what do they require?
Transporters move ions and chemicals against their electrochemical (concentration/voltage) gradient
This requires energy provided by ATP hydrolysis “active transport”
40
what are the 2 types of active transport?
1)Primary active transport: “direct”
2) Secondary active transport (co-transport )
-does not directly require a chemical source
of energy such as ATP.
* uses an electrochemical gradient – generated
by primary active transport
* Ion is then transported back together with
and additional molecule (e.g. serotonin (5-HT),
co-transport)
41
how do some drugs act on transporters e.g. antidepressants (3 potential ways)
Antidepressant aim = To increase the amount of serotonin (5-HT) (neurotransmitter )at the receptor
1. Block the enzyme clearance of serotonin (stop serotonin from being broken down by enzymes in the synpase)
2. Increase the amount of serotonin in the brain by taking drugs
3. Boost the effects of serotonin (5-HT) by blocking transporter re-uptake
42
briefly explain the way fluoxetine (antidepressant) works
Action potential, calcium channels open, serotonin released into synapse cleft, then binds to g protein couple receptors or ligand gated ion channels and this causes improvement in mood. We need to get rid of this serotonin in order to recycle it back into vesicles so were not continuously happy as we need balance in life. The body does this by transporting it back into vesicles done by a transporter with another molecule, sodium.
Prozac (drug containing fluoxetine) blocks the transporter that once allowed serotonin to be removed from synapse. This means serotonin stays in synaptic cleft which increases the chance of serotonin binding to its own receptors that increases humans’ moods
43
what can happen when drugs act on enzymes?
* Most drugs acting at enzymes are inhibitors (not antagonists as these are enzymes not receptors)
* Drugs can also potentiate enzymes (i.e. increase their activity) (false substrate)
* Drugs can be converted from their inactive from to their active form. Can be positive or negative (e.g. pro-drugs masks being removed)
44
example of anticholinesterases and anaesthesia
* In general anaesthesia the action of nicotinic ACh receptors is blocked to stop movement (NEUROMUSCULAR BLOCK)
* At the end of surgery, the effect of these neuromuscular blockers is reversed by anti-cholinesterase’s: e.g. neostigmine
* These inhibit cholinesterase, prevent ACh breakdown, and therefore increase ACh concentration within synapse
* This displaces the receptor blocker (anaesthetic) from the receptor, reversing its effect.
Reverses muscle relaxation and cause patient to become conscience after surgery
45
what is signal transduction?
the process by which a cell receives and responds to external signals, such as chemical or physical stimuli, to perform a specific function
46
what is a pro-drug?
A precursor (forerunner) of a drug.
A prodrug must undergo chemical conversion within the body before becoming an
active pharmacological agent
a pro drug is basically an active drug that has been masked. The mask can be removed by enzymes which then allows the drug to take effect
47
Why do we have prodrugs?
-To enable a drug to be formulated correctly
-To enhance solubility of the drug
-To minimise excretion form the body
-To enhance stability of the chemical
-To target the drug to a specific area (e.g. if you want the drug to work/take effect in the lungs then it would be ideal for the unmasking enzyme to be present in the lungs )
48
1)WHAT IS LEVODOPA USED TO TREAT AND HOW DOES IT EXERT ITS EFFECT?
In Parkinson’s there are reduced levels of the neurotransmitter dopamine in certain brain areas (e.g. basal ganglia)
Therefore, to counter symptoms of lack of movement, rigidity and tremor, a therapeutic aim is to restore dopamine levels in the brain.
The deficiency cannot be treated with dopamine itself , as it does not cross the blood-brain barrier (can’t diffuse across membrane) and so doesn’t reach target tissue of the brain
Levodopa, or L-DOPA is used instead – WHY?
L-DOPA is the immediate precursor to dopamine in the
biosynthetic pathway (endogenous) (L-dopa has ability to cross blood brain barrier as it mimics amino acids)
So dopamine with l-dopa at the front can enter into the brain, then dopa decarboxylase is present which removes the L-dopa mask and dopamine levels rise.
49
Carbidopa is an inhibitor of DOPA decarboxylase.
Why is it used in combination with L-DOPA?
Carbidopa inhibits DOPA decarboxylase (stops l-dopa mask being removed from dopamine). We use carbidopa with L-DOPA drug because carbidopa cannot cross the blood-brain barrier into the brain and therefore only works in the blood outside the brain. This is beneficial as it means less l-DOPA masks are removed from dopamine outside the brain which is good because dopamine itself cannot get into the brain without L-DOPA. In the long run helps reduce symptoms as more dopamine can actually get into the brain
50
why are dose response curves helpful for pharmacologists?
helps:
Drug discovery programs
Predict safe therapeutic doses
Minimise side effects/adverse effects
51
longer definition of pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body, the mechanisms of drug action and the relationship between drug concentration and effect.
* Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.
52
what are agonists & antagonists competing for?
empty receptors
53
why are agonists and antagonists reversible?
Agonists have to be able to disassociate from the receptor otherwise the drug-receptor complex would be in place for ever and a constant response produced
54
what happens if agonist concentration is increased? (in regards to antagonists and agonists on receptors)
if agonist concentration is increased it will displace an antagonist from the receptor (competitive)
55
what is size of response dependent on?
concentration of drug
56
what is the dose response curve for an agonist called? and what is important about the EC50?
Hyperbolic curve
not very accurate for finding EC50 as very close to axis & therefore not very useful for pharmacologists. Log graph is a lot more common as more useful
57
what is a log dose-response curve for an agonist called? and what are its advantages?
sigmoidal curve
The central portion (20-80% response) is a straight line, allows easy calculation of EC50
* when a small change in concentration produces a relatively large change in response – this is easier to measure in a log plot
* Easier to compare relative potency of agonists e.g. measure EC50 (concentration giving 50% response)
58
what is the difference between full and partial agonists?
* Full agonists are drugs whose maximum response is the largest a tissue or cell is capable of giving (i.e. they have high efficacy) (100% response on a response curve. Graph line reaches top, Cmax)
* Partial agonists are drugs whose maximum response is lower than this (even when they occupy all the available receptors) they never reach 100% response. Graph line is always underneath the top Cmax
59
what effect does potency have on the response curve?
If the curve is shifted to the left, it has high potency. If shifted to right is has low potency.
60
what effect does efficacy have on the response curve?
On vertical plane (up or down) if curve is high up it has high efficacy. If curve is low, it has lower efficacy
61
A competitive antagonist can be displaced from the receptor by increasing the concentration of the agonist
Atropine is a competitive antagonist. . It blocks the binding of acetylcholine (Ach) to muscarinic Ach receptors
Every time you add more of the competitive antagonist, the curve moves parallel right. This is because the antagonists are taking more spaces and blocking agonists. This means there is less response and therefore higher concentration of acetylcholine is needed across the bottom of graph
OTHER ACTIONS AT ACH RECEPTORS
* Propiverine is a non-competitive antagonist (acts on another site of receptor, not the active site, and so agonist can still bind) of the actions of Ach at muscarinic receptors
* Propiverine acts at another site to prevent the effects of stimulation of the muscarinic receptor by Ach
62
what do all antagonists do to the dose response curve?
All antagonists shift the dose response curve of an agonist to the right
63
what effects does a competitive antagonist have on the dose-response curve?
For a competitive antagonist (e.g. atropine) the maximal response remains the same, and response curves are shifted in a parallel manner
–competitive antagonists bind at the same site as agonists, and can be displaced by agonist
64
what effects does a non-competitive antagonist have on the dose-response curve?
For a non-competitive antagonist (e.g. propiverine) the maximal response to the agonist is reduced, and the curve is not parallel to that of the agonist alone
– non-competitive antagonists bind at another site (i.e. not the site to which the agonist binds)
65
what is the difference between classical drug discovery and modern day drug discovery?
classic:
1)does not require knowledge of the target of the drug in molecular or cellular terms
2)the method used to test activity is on a whole organism/animal thefore cannot look at million of molecules
modern:
1)requires knowledge of the target of the drug in molecular or cellular terms
2)the method used to test activity is on proteins, cells then later whole organisms therefore looks at million of molecules
65
what are some problems with modern day drug discovery?
Expensive and high-risk business
* Average cost to the point of marketing approval including compound abandoned during development is approx. $2.55 billion dollars
* 10-15 years to develop (patent only last 20 years)
* High attrition rate
* only 1 in 10 drugs that start the clinical phases will make it to market
* 90% fail!! Why?:
* lack of clinical efficacy (40%–50%) (works in labs nor humans)
* unmanageable toxicity (30%)
* poor drug-like properties (10%–15%) (drug doesn’t get to target in human)
* lack of commercial needs and poor strategic planning (10%) (too much competition etc)
66
what are the regulations when making drugs?
Each drug must be safe and efficacious and manufactured to high quality standards
* Efficacy must be proven across ethnicities as well as across different age groups (depending on target population)
* Each drug must pass regulatory review by the specific governing body from each individual market territory
* MHRA (UK), EMA (EU), FDA (USA) to name a few.
* Approved drugs must appeal to global markets across different healthcare systems and distribution systems
67
what are the 3 main stages of development of new small molecule drugs
1)Drug discovery
2)Preclinical development
3)Clinical development
-Includes Phase I-III, regulatory approval and
Pharmacovigilance (Phase IV)
68
what kind of collaboration is needed for drug discovery?
integrative collaboration- between experts from multiple disciplines under the umbrella of Biosciences
69
Selecting therapeutic areas to invest in is driven by:
* Therapeutic need (is there a need for a drug i.e. is there already a drug on the market )
* Prevalence of disease (if more people have disease, more reason to make more drugs )
* Likelihood of success
-Success rate varies between therapeutic areas
-Central nervous system drugs have the lowest success rates
70
what are additional considerations when choosing drugs to invest in?
* Technical feasibility (penicillin story-scaling up) (basically can you make lots of the drug, enough for commercial viability)
* Research and development costs
* Commercial considerations
* Competition
* Market share
71
what is the first step in drug discovery? and what does it require?
target identification
* Requires extensive knowledge of the fundamental underlying biological mechanisms driving the disease progression
72
what is the second step in drug discovery?
screening and lead identification
* Once you have identified your target you need to begin search to identify suitable chemicals to interact with the target and have the desirable biological effect.
* Early chemical starting points are:
- Naturally occurring molecules (plants,
humans, animals)
- Targeted chemical synthesis (compound libraries) companies have enormous compound libraries, and each patent them. Companies will have millions of molecules stored that they can use and put into bioassays to see if any of the compounds have efficacy and biological response.
73
what are the 2 ways you an screen compounds from compound libraries?
1)High throughput screening (HTS)
* screening of the entire chemical
compound library against the drug target
(usually over 100k molecules ) Basically they use every single compound with the drug target to see if any molecule comes up with a response
2)In-silico ‘virtual’ screening
* selecting from the chemical compound
library, smaller subsets of chemicals with
potential activity at the target protein in a
computational model You know the target and you know the dynamics of the active site of the target so you programme a computer to predict how molecules from the compound library will bind with target receptor. Saves actually having to do the screening in person.
74
what happens after screening of compound libraries? (hits and active leads)
After screening you get a number of hits
* ‘Hits’ chemicals are characterised to confirm if they are ‘biologically active’ and not false positives. This is done by doing dose responses. They are then called active leads
* ‘Active’ leads are optimised chemically to improve safety, efficacy and pharmacokinetic properties. (improve chemical structures)
75
what happens in preclinical development and how is it done?
Build a profile of the efficacy and safety of the drug candidate and potential safety liabilities that can be monitored in the clinic
* Informs regulatory bodies decision to progress to FIH trial (first into human) basically building picture of chemical and whether its safe
In vivo and invitro testing
In vitro cell modelling (petri dishes etc)
Ex vivo = more complex testing, more than one cell line
In vivo = tested on rodents
76
what is the overview of clinical development and what happens in phases I, II, III?
it is the Translation of preclinical data to establish first in man dosing (what size dose to use in humans) (FIM)
Phase I:
* Usually Healthy volunteers
* 10-80 people
* Very low starting dose
* PK/PD, Safety, tolerability, and dose ranging studies
(the only time you would use a non-healthy volunteer is if they are going to die anyway. But also, in cases such as chemotherapy – you wouldn’t give a healthy person chemo and so would use an ill patient with cancer)
Phase II:
Cohort of patients with target disease
Establish efficacy (is the drug taking effect?) and dose-response relationship safety
Phase III: Pivotal studies
Large cohort of patients with target disease
Large scale safety and efficacy confirmation studies
only 1 in 10 drugs that start the clinical phases will make it to market
77
what is the purpose of Regulatory approval and after-market monitoring?
* Each drug must demonstrate safety and efficacy in the intended patient population
* Benefits of the drug must out-weigh the risks
*Strict regulatory standard govern the conduct of:
-Pre-clinical development
-Clinical trials
-Manufacturing
78
what is phase IV of clinical development?
Post marketing safety (Phase IV or pharmaco-vigilance) studies long term risks, by monitoring adverse events in the wider population
79
what occurs in Drug life cycle management/ why is it needed?
* Pharmaceutical company will design a life cycle for the drug throughout the start of drug design phase/patent life and beyond into the generic market
* when the patent runs out, companies come up with different ways of marketing the drug such as Different drug delivery systems (prolonged release vs immediate release e.g. take drug once a week rather than every day)
* Combinations with other drugs for improved efficacy
* New indications (repurposing)
* Adapting an existing drug for a new therapy (repurposing)
80
list the emerging technologies for drug discovery
-AI
-new modalities
-PROTACS (small molecules)
-protein therapeutics
-Biologics
-Gene therapy
-stem cell therapy
81
what does AI have potential to improve and what are some negatives?
* Speed, efficiency, and cost
* Analyse and process enormous amounts of data
* better informed, less biased decisions.
* Example: High throughput screening
100k + --> millions compounds virtually
* Allows the exploration of the broader chemical space and suggest potential active structural leads not in the company's library.
However:
* Relies on sufficient quality and volume of data to be ‘trained’
* Without this unreliable and inaccurate
82
Small molecules - PROTACS
* Therapeutics that degrade proteins using the body’s natural processes to degrade disease causing proteins
* A number of PROTACS are under evaluation in clinical trials
* Preliminary data have shown encouraging clinical activity in patients with prostate cancer, breast cancer and chronic lymphocytic leukaemia
83
why are protein therapeutics advantageous over small molecule drugs?
Protein therapeutics have several advantages over small-molecule drugs
Biological reasons:
1. Proteins often serve a highly specific and complex set of functions that cannot be mimicked by simple chemical compounds
2. Because the action of proteins is highly specific, there is often less potential for protein therapeutics to interfere with normal biological processes and cause adverse effects
3. For diseases in which a gene is mutated or deleted, protein therapeutics can provide effective replacement treatment without the need for gene therapy, which is not currently available for most genetic disorders
84
what are biologics?
* Therapeutics that replace a protein that is deficient or abnormal
e.g. Insulin – Diabetes
* Therapeutics that interfere with a protein molecule
Trastuzumab (Herceptin) – Antibody therapy binds HER2 receptors and controls breast cancer cell growth
85
what is gene therapy/ stem cell therapy?
* Replace of a faulty gene or activation of silenced gene
* Zolgensma: Gene therapy for Spinal Muscular Atrophy
86
what is cell therapy for cancer?
T cells are immune cells used to attack tumours. Sometimes tumours become resistant to this immune response. You can take T cells and reprogramme them to become reactivated and carry on attacking the tumour. (called CAR-T-cell therapy)
